Attenuation of persistent pain-related behavior by fatty acid amide hydrolase (FAAH) inhibitors in a rat model of HIV sensory neuropathy

Abstract

Distal sensory neuropathies are a hallmark of HIV infections and can result in persistent and disabling pain despite advances in antiretroviral therapies. HIV-sensory neuropathic (HIV-SN) pain may be amenable to cannabinoid treatment, but currently available agonist treatments are limited by untoward side effects and potential for abuse in this patient population. Fatty acid amide hydrolase (FAAH) inhibitors may offer an alternative approach by inhibiting the degradation of endocannabinoids with purportedly fewer untoward CNS side effects. In order to evaluate this potential approach in the management of HIV-SN pain, the recombinant HIV envelope protein gp120 was applied epineurally to the rat sciatic nerve to induce an HIV-SN-like pain syndrome. Two distinct FAAH inhibitory compounds, URB597 and PF-3845 were tested, and contrasted with standard antinociceptive gabapentin or vehicle treatment, for attenuation of tactile allodynia, cold allodynia, and mechanical hyperalgesia. Both FAAH inhibitors markedly reduced cold and tactile allodynia with limited anti-hyperalgesic effects. Peak antinociceptive effects produced by both agents were more modest than gabapentin in reducing tactile allodynia with similar potency ranges. URB597 produced comparable cold anti-allodynic effects to gabapentin, and the effects of both FAAH inhibitors were longer lasting than gabapentin. To assess the contribution of cannabinoid receptors in these antinociceptive effects, CB1 antagonist AM251 or CB2 antagonist SR144528 were tested in conjunction with FAAH inhibitors. Results suggested a contribution of both CB1- and CB2-mediated effects, particularly in reducing tactile allodynia. In summary, these findings support inhibition of endocannabinoid degradation as a promising target for management of disabling persistent HIV-SN pain syndromes.

Nociceptor plasticity: A closer look

“…The inhibition of FAAH has been widely investigated in animal models as it appears to be a promising target for pharmacological interventions; it also documents Endocannabinoids role in pain perception both in physiological and pathological settings. FAAH inhibition was also found effective to reduce cold and mechanical allodynia and mechanical hyperalgesia in a murine model of HIV-induced sensory neuropathy (Nasirinezhad, Jergova, Pearson, & Sagen, 2015); both CB1 and CB2 appeared to be responsible for the anti-nociceptive effects of the FAAH inhibitors.…”

“…The inhibition of FAAH has been widely investigated in animal models as it appears to be a promising target for pharmacological interventions; it also documents Endocannabinoids role in pain perception both in physiological and pathological settings. FAAH inhibition was also found effective to reduce cold and mechanical allodynia and mechanical hyperalgesia in a murine model of HIV‐induced sensory neuropathy (Nasirinezhad, Jergova, Pearson, & Sagen, ); both CB1 and CB2 appeared to be responsible for the anti‐nociceptive effects of the FAAH inhibitors. Finally, the role of FAAH in pain perception was also investigated in humans: FAAH Single Nucleotide Polymorphisms were assessed in a group of women undergoing breast cancer surgery, and some mutations responsible for lower FAAH activity were associated to less cold pain sensitivity and less need for post‐operative analgesia (Cajanus et al, ).…”

P2Y12 receptor upregulation in satellite glial cells is involved in neuropathic pain induced by HIV glycoprotein 120 and 2′,3′-dideoxycytidine

“…HIV-gp120 also has direct and indirect effects on nerves by stimulating the nervous system to release pro-inflammatory cytokines [1,22,31,32]. Pro-inflammatory cytokines can activate SGCs, as a feedback, SGC activation may cause more release of pro-inflammatory cytokines, that will increase abnormal neuronal excitability and contribute to neuropathic pain.…”

“…The pressure value was automatically recorded. Measurements were performed 2-3 times for each rat (interval ≥ 5 min), and the mechanical withdrawal threshold was calculated as the mean of these measurements [21][22][23][24].…”

“…The latency to hind paw withdrawal from a thermal stimulus was determined by exposing the plantar surface of the hind paw to radiant heat using a Thermal Paw Stimulation System (BME-410C, Tianjin) [21][22][23][24]. Rats were placed in a transparent, square, bottomless acrylic box (22 × 12 × 22 cm) on a glass plate with a light located underneath.…”